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- PDB-9mhw: Human TLR8 ectodomain with small molecule agonist 9 -

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Basic information

Entry
Database: PDB / ID: 9mhw
TitleHuman TLR8 ectodomain with small molecule agonist 9
ComponentsToll-like receptor 8
KeywordsIMMUNE SYSTEM / Toll-like receptor 8 / agonist
Function / homology
Function and homology information


Toll Like Receptor 7/8 (TLR7/8) Cascade / toll-like receptor 8 signaling pathway / negative regulation of interleukin-12 production / endolysosome membrane / positive regulation of innate immune response / Trafficking and processing of endosomal TLR / toll-like receptor signaling pathway / pattern recognition receptor activity / positive regulation of interferon-alpha production / immunoglobulin mediated immune response ...Toll Like Receptor 7/8 (TLR7/8) Cascade / toll-like receptor 8 signaling pathway / negative regulation of interleukin-12 production / endolysosome membrane / positive regulation of innate immune response / Trafficking and processing of endosomal TLR / toll-like receptor signaling pathway / pattern recognition receptor activity / positive regulation of interferon-alpha production / immunoglobulin mediated immune response / canonical NF-kappaB signal transduction / positive regulation of interferon-beta production / positive regulation of interleukin-1 beta production / positive regulation of interleukin-8 production / response to virus / positive regulation of interleukin-6 production / positive regulation of type II interferon production / cellular response to mechanical stimulus / double-stranded RNA binding / signaling receptor activity / defense response to virus / positive regulation of canonical NF-kappaB signal transduction / single-stranded RNA binding / endosome membrane / inflammatory response / Golgi membrane / external side of plasma membrane / innate immune response / endoplasmic reticulum membrane / SARS-CoV-2 activates/modulates innate and adaptive immune responses / DNA binding / RNA binding / identical protein binding / plasma membrane
Similarity search - Function
TIR domain / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Toll - interleukin 1 - resistance / TIR domain profile. / Leucine-rich repeat, SDS22-like subfamily / Toll/interleukin-1 receptor homology (TIR) domain / Toll/interleukin-1 receptor homology (TIR) domain superfamily / Leucine rich repeat / Leucine-rich repeat, typical subtype ...TIR domain / Cysteine-rich flanking region, C-terminal / Leucine rich repeat C-terminal domain / Toll - interleukin 1 - resistance / TIR domain profile. / Leucine-rich repeat, SDS22-like subfamily / Toll/interleukin-1 receptor homology (TIR) domain / Toll/interleukin-1 receptor homology (TIR) domain superfamily / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Leucine-rich repeat / Leucine-rich repeat domain superfamily
Similarity search - Domain/homology
: / NICKEL (II) ION / Toll-like receptor 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.52 Å
AuthorsCritton, D.A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2025
Title: Structure-Based Design of Novel TLR7/8 Agonist Payloads Enabling an Immunomodulatory Conjugate Approach.
Authors: Poudel, Y.B. / Lo, J.C. / Norris, D.J. / Cox, M. / He, L. / Johnson, W.L. / A M Subbaiah, M. / Mondal, S. / Thangavel, S. / Subramani, L. / Reddy, M. / Jain, S. / Weiss, D.R. / Sivaprakasam, ...Authors: Poudel, Y.B. / Lo, J.C. / Norris, D.J. / Cox, M. / He, L. / Johnson, W.L. / A M Subbaiah, M. / Mondal, S. / Thangavel, S. / Subramani, L. / Reddy, M. / Jain, S. / Weiss, D.R. / Sivaprakasam, P. / Critton, D. / Mulligan, D. / Xie, C. / Dhar, P. / Li, Y. / Sega, E. / Yamazoe, S. / Gavai, A.V. / Mathur, A. / Zapf, C.W. / Chekler, E.P.
History
DepositionDec 12, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 5, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Toll-like receptor 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)97,12215
Polymers92,3081
Non-polymers4,81414
Water15,529862
1
A: Toll-like receptor 8
hetero molecules

A: Toll-like receptor 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)194,24430
Polymers184,6162
Non-polymers9,62928
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Unit cell
Length a, b, c (Å)140.073, 100.530, 77.913
Angle α, β, γ (deg.)90.00, 121.86, 90.00
Int Tables number5
Space group name H-MC121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Toll-like receptor 8


Mass: 92307.766 Da / Num. of mol.: 1 / Fragment: residues 27-827
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TLR8, UNQ249/PRO286 / Production host: Drosophila melanogaster (fruit fly) / References: UniProt: Q9NR97

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Sugars , 3 types, 12 molecules

#2: Polysaccharide alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(2-6)]beta-D- ...alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(2-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1072.964 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-2DManpa1-3[DManpa2-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{[(2+1)][a-D-Manp]{}}[(6+2)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#3: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}}LINUCSPDB-CARE
#4: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 9
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 3 types, 864 molecules

#5: Chemical ChemComp-NI / NICKEL (II) ION


Mass: 58.693 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ni
#6: Chemical ChemComp-A1BLT / (3S)-3-[(2-amino-5-{[2-methoxy-5-({[(3S)-oxolan-3-yl]amino}methyl)phenyl]methyl}-5H-pyrimido[5,4-b]indol-4-yl)amino]hexan-1-ol


Mass: 518.650 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H38N6O3 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 862 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.52 Å3/Da / Density % sol: 51.26 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
Details: 0.2 M magnesium formate, 20% (w/v) PEG 3,350, 0.1 M manganese tetrachloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.9655 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Sep 11, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9655 Å / Relative weight: 1
ReflectionResolution: 1.51→66.18 Å / Num. obs: 234030 / % possible obs: 82.5 % / Redundancy: 3.2 % / CC1/2: 0.999 / Net I/σ(I): 11.8
Reflection shellResolution: 1.51→1.71 Å / Mean I/σ(I) obs: 1.9 / Num. unique obs: 9519 / CC1/2: 0.79

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Processing

Software
NameVersionClassification
XDSdata reduction
XDSdata scaling
PHASERphasing
BUSTER2.11.8 (3-FEB-2022)refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.52→66.18 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.926 / SU R Cruickshank DPI: 0.222 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.158 / SU Rfree Blow DPI: 0.139 / SU Rfree Cruickshank DPI: 0.136
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION.
RfactorNum. reflection% reflectionSelection details
Rfree0.23 3908 5.32 %RANDOM
Rwork0.197 ---
obs0.199 73435 51.7 %-
Displacement parametersBiso mean: 19.95 Å2
Baniso -1Baniso -2Baniso -3
1--1.0681 Å20 Å2-0.4452 Å2
2--4.3214 Å20 Å2
3----3.2533 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: LAST / Resolution: 1.52→66.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5936 0 314 862 7112
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00812654HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0322886HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3902SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes2038HARMONIC5
X-RAY DIFFRACTIONt_it6475HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.54
X-RAY DIFFRACTIONt_other_torsion15.96
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion923SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact11049SEMIHARMONIC4
LS refinement shellResolution: 1.52→1.65 Å
RfactorNum. reflection% reflection
Rfree0.2779 -4.7 %
Rwork0.2475 1400 -
obs--4.76 %
Refinement TLS params.Method: refined / Origin x: 11.6573 Å / Origin y: -9.2845 Å / Origin z: 16.3091 Å
111213212223313233
T-0.0572 Å20.0047 Å2-0.0036 Å2-0.0167 Å20.009 Å2---0.099 Å2
L0.0707 °2-0.0664 °20.0125 °2-0.1071 °20.0581 °2--0.0493 °2
S0.0129 Å °-0.0214 Å °-0.0898 Å °-0.0084 Å °-0.003 Å °0.0075 Å °0.0489 Å °-0.0083 Å °-0.0099 Å °
Refinement TLS groupSelection details: { A|* }

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